rs7190823

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000135.4(FANCA):c.796A>G(p.Thr266Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.46 in 1,607,974 control chromosomes in the GnomAD database, including 184,200 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T266M) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.53 ( 23670 hom., cov: 33)

Exomes 𝑓: 0.45 ( 160530 hom. )

Consequence

FANCA
NM_000135.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13O:1

Conservation

PhyloP100: 0.671

Publications

86 publications found

Variant links:

Genes affected

FANCA (HGNC:3582): (FA complementation group A) The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2). The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group A. Alternative splicing results in multiple transcript variants encoding different isoforms. Mutations in this gene are the most common cause of Fanconi anemia. [provided by RefSeq, Jul 2008]

FANCA Gene-Disease associations (from GenCC):

Fanconi anemia complementation group A
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P
Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

FANCA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.1698945E-6).

BP6

Variant 16-89799635-T-C is Benign according to our data. Variant chr16-89799635-T-C is described in ClinVar as [Benign]. Clinvar id is 134294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.959 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCA	NM_000135.4 link	c.796A>G	p.Thr266Ala	missense_variant	Exon 9 of 43	ENST00000389301.8	NP_000126.2	O15360-1
FANCA	NM_001286167.3 link	c.796A>G	p.Thr266Ala	missense_variant	Exon 9 of 43		NP_001273096.1	O15360-3
FANCA	NM_001018112.3 link	c.796A>G	p.Thr266Ala	missense_variant	Exon 9 of 11		NP_001018122.1	O15360-2
FANCA	NM_001351830.2 link	c.700A>G	p.Thr234Ala	missense_variant	Exon 8 of 10		NP_001338759.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCA	ENST00000389301.8 link	c.796A>G	p.Thr266Ala	missense_variant	Exon 9 of 43	1	NM_000135.4	ENSP00000373952.3		O15360-1

Frequencies

GnomAD3 genomes

AF:

0.531

AC:

80719

AN:

152034

Hom.:

23636

Cov.:

show subpopulations

Gnomad AFR

AF:

0.717

Gnomad AMI

AF:

0.304

Gnomad AMR

AF:

0.544

Gnomad ASJ

AF:

0.327

Gnomad EAS

AF:

0.981

Gnomad SAS

AF:

0.628

Gnomad FIN

AF:

0.474

Gnomad MID

AF:

0.225

Gnomad NFE

AF:

0.399

Gnomad OTH

AF:

0.465

GnomAD2 exomes

AF:

0.521

AC:

130900

AN:

251338

AF XY:

0.509

show subpopulations

Gnomad AFR exome

AF:

0.725

Gnomad AMR exome

AF:

0.668

Gnomad ASJ exome

AF:

0.320

Gnomad EAS exome

AF:

0.984

Gnomad FIN exome

AF:

0.469

Gnomad NFE exome

AF:

0.385

Gnomad OTH exome

AF:

0.454

GnomAD4 exome

AF:

0.453

AC:

658793

AN:

1455822

Hom.:

160530

Cov.:

AF XY:

0.454

AC XY:

328778

AN XY:

724642

show subpopulations

African (AFR)

AF:

0.723

AC:

24115

AN:

33344

American (AMR)

AF:

0.653

AC:

29193

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.323

AC:

8421

AN:

26098

East Asian (EAS)

AF:

0.980

AC:

38877

AN:

39670

South Asian (SAS)

AF:

0.589

AC:

50746

AN:

86148

European-Finnish (FIN)

AF:

0.461

AC:

24611

AN:

53354

Middle Eastern (MID)

AF:

0.333

AC:

1921

AN:

5762

European-Non Finnish (NFE)

AF:

0.409

AC:

452720

AN:

1106550

Other (OTH)

AF:

0.468

AC:

28189

AN:

60192

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

15617

31234

46852

62469

78086

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.531

AC:

80814

AN:

152152

Hom.:

23670

Cov.:

AF XY:

0.540

AC XY:

40187

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.717

AC:

29755

AN:

41508

American (AMR)

AF:

0.545

AC:

8320

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.327

AC:

1135

AN:

3468

East Asian (EAS)

AF:

0.981

AC:

5095

AN:

5192

South Asian (SAS)

AF:

0.628

AC:

3028

AN:

4818

European-Finnish (FIN)

AF:

0.474

AC:

5008

AN:

10576

Middle Eastern (MID)

AF:

0.238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.399

AC:

27132

AN:

67994

Other (OTH)

AF:

0.471

AC:

994

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

1787

3575

5362

7150

8937

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.444

Hom.:

60668

Bravo

AF:

0.547

TwinsUK

AF:

0.436

AC:

1616

ALSPAC

AF:

0.409

AC:

1576

ESP6500AA

AF:

0.726

AC:

3190

ESP6500EA

AF:

0.394

AC:

3386

ExAC

AF:

0.516

AC:

62710

Asia WGS

AF:

0.788

AC:

2740

AN:

3478

EpiCase

AF:

0.384

EpiControl

AF:

0.372

ClinVar

Significance: Benign

Submissions summary: Benign:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fanconi anemia complementation group A

Benign:6

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 19, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 08, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2Other:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 03, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

not provided

Benign:2

Mar 01, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 23021409, 24728327, 27153395) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Inborn genetic diseases

Benign:1

Oct 22, 2019

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Fanconi anemia

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Malignant tumor of breast

Benign:1

Center of Medical Genetics and Primary Health Care

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.046

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.51

CADD

Benign

7.2

(source)

DANN

Benign

0.16

DEOGEN2

Benign

0.072

T;.;.;T;T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0032

LIST_S2

Benign

0.023

T;T;T;T;T;T

MetaRNN

Benign

0.0000012

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-2.1

N;N;N;.;.;.

PhyloP100

0.67

PrimateAI

Benign

0.42

PROVEAN

Benign

1.7

N;N;N;N;N;N

REVEL

Benign

0.084

Sift

Benign

1.0

T;T;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T;T

Polyphen

0.0

B;.;B;.;B;B

Vest4

0.086

ClinPred

0.0032

GERP RS

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.017

gMVP

0.078

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.19

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs7190823

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over